1. Field of the Invention
The invention is generally related to the therapeutic use of xcex949 Tetrahydrocannabinol (xcex949 THC). In particular, the invention provides a metered dose inhaler (MDI) for the aerosol administration of xcex949 THC to patients suffering from nausea and vomiting associated with cancer chemotherapy, muscle spasticity, pain, anorexia associated with AIDS wasting syndrome, epilepsy, glaucoma, bronchial asthma, mood disorders, and the like.
2. Background Description
In 1997, the National Institutes of Health (NIH) released a review of the scientific data concerning potential therapeutic uses for marijuana. In that review, the NIH found that marijuana may indeed have beneficial medicinal effects and recommended that researchers develop alternative dosage forms for the drug, such as a xe2x80x9csmoke freexe2x80x9d inhaled delivery system. Workshop on the medical utility of marijuana, National Institutes of Health, August 1997. Studies have documented therapeutically beneficial medicinal uses of the major active component of marijuana, xcex949 tetrahydrocannabinol (xcex949 THC). Beal, J. A., Olson, R., Lefkowitz, L., Laubenstein, L., Bellman, P., Yangco, B., Morales, J. O., Murphy, R., Powderly, W., Plasse,.T. F., Mosdell, K. W. and Shepard, K. W., Long-term efficacy and safety of dronabinol for acquired immnunodeficiency syndrome-associated anorexia, J Pain. Symptom Manage. 14:7-14 (1997); Beal, J. A., Olson, R., Laubenstein, L., Morales, J. O., Beliman, B., Yangco, B., Lefkowitz, L., Plasse, T. F. and Shepard, K. V. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS, J Pain. Symptom Manage,. 10:89-97 (1995); McCabe, M., Smith, F. P., MacDonald, J. S., Wooley, P. V., Goldberg, D. and Schein, P. S., Efficacy of tetrahydrocannabinol in patients refractory to standard antiemetic therapy, Invest. New Drugs 6:243-246 (1988); Lucas, V. S. and Laszlo, J. xcex949-THC for refractory vomiting induced by cancer chemotherapy, JAMA 243:1241-1243 (1980); Sallan, S. E., Cronin, C., Zelen, M. and Zinberg, N. E., Antiemetics in patients receiving chemotherapy for cancer: a randomized comparison of xcex949 THC and prochlorperazine, N. Engl. J Med., 302:135-138 (1980); Frytak, S., Moertel, C. G., O""Fallon, J R., Rubin, J., Creagan, E.T., O""Connell, M. J., Schutt, A. J. and Schwartau, N. W., Delta-9-tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy: a comparison with prochlorperazine and a placebo, Ann. Inter. Med 91:825-830 (1979); Chang, A. E., Shiling, D. J., Stillman, R. C., Goldgerg, N. H., Seipp, C.A., Barofdky, I., Simon, R. M. and Rosenberg S A, xcex949 THC as an antiemitic in cancer patients receiving high-dose methotrexate. Ann. Internal Med. 91:819-824 (1979); Sallan, S. E., Zinberg, N. E. and Frei, I.E., Antiemetic effect of xcex949 THC in patients receiving cancer chemotherapy, New Engl. J Med. 293:795-797 (1975); Noyes, J R., Brunk, S. F., Baram, D. A. and Canter, A., The analgesic properties of xcex949 THC and codeine. J Clin. Pharmacol 15:139-143 (1975); Noyes, R., Jr., Brunk, S. F., Baram, D. A. and Canter, A., Analgesic effect of xcex949 tetrahydrocannabinol, Clin. Pharmacol and Ther 18:84-89 (1975); Brenneisen, R., Egli, A., Elosohlly, M. A., Henn, V. and Spiess, Y., The effect of orally and rectally administered xcex949 THC on spasticity: a pilot study with 2 patients, Int. J Clin. J Pharmocol Ther. 34:446-452 (1996); Ungerleider, J. T., Andyrsiak, T. F. L., Ellison, G. W. and Myers, L. W., xcex949 THC in the treatment of spasticity associated with multiple sclerosis, Adv. Alcohol Subst. Abuse 7:39-50 (1987); Clifford, D. B., Tetra-hydrocannabinol for tremor in multiple sclerosis, Ann. Neurol 13:669-171 (1983); Petro, D. J. and Ellenberger, C., Treatment of human spasticity with delta 9 -tetrahydrocannabinol, J Clin. Pharmacol 21:413S-416S (1981); Maurer, M., Henn, V., Dittrich, A. and Hofman, A., Delta 9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial, Eur. Arch. Psychiatry Neurol Sci. 240:1-4 (1990); Merritt, J., Crawford, W., Alexander, P., Anduze, A. and Gelbart, S., Effects of marijuana on intra ocular and blood pressure in glaucoma, Opht. 87:222-228 (1980); Cooler, P. and Gregg, J. M., Effect of delta 9-xcex949 THC on intra ocular pressure in humans. South. Med J 70:951-954 (1977). Table 1 summarizes the findings of these studies.
The year after the 1997 NIH study, the House of Lords made a recommendation to the British government (House-of-Lords-Select-Committee-on-Science-and-Technology, 1998) to reschedule marijuana. Similarly, there have been efforts to decriminalize marijuana in the United States.
When marijuana is used as a recreational psychoactive drug, the active ingredient xcex949 THC is usually delivered to the lungs as an impure non-pharmaceutical aerosol in the form of marijuana smoke. Aerosolized xcex949 THC in the inhaled smoke is absorbed within seconds and delivered to the brain efficiently. The pharmacokinetics of the administration of xcex949 THC is described in PDR Physician""s Desk Reference (49) Montvalek, New Jersey: Medical Economics Data Production Co. (1995), pp.2787; Ohlsson, A., Lindgren J. E., Wahlen, A., Agurall, S., Hollister, L. E. and Gillespie, H. K., Plasma xcex949 THC concentrations and effects after oral and intravenous administration and smoking, Clin. Phamacol Ther. 28:409-416 (1980), summarized in Table 2 below. As can be seen, inhalation is the preferred route of delivery for xcex949 THC. When compared to oral delivery, inhalation provides a more rapid onset of pharmacological action and peak plasma levels. The effects achieved via inhalation are comparable to those achieved when the drug is administered intravenously, but inhalation is a much less invasive technique.
Currently, the sources of xcex949 THC for patients who could benefit from the drug are limited. An oral form of xcex949 THC (MARINOL) is marketed as a treatment for nausea and vomiting related to cancer chemotherapy, and as an appetite stimulant in patients suffering from AIDS wasting syndrome. In MARINOL, pharmaceutical grade xcex949 THC is dissolved in sesame oil, encapsulated in gelatin capsules and delivered orally. However, when the drug is taken orally, the absorption is slower and more variable than when inhaled, with an onset of action between 30 minutes and 2 hours (Table 2). Drawbacks of MARINOL include its slow onset of action and extensive first-pass metabolism (Mattes, R. D. Shaw, L. M., Edling-Owens, J., Engelman, K., Elsohly, M. A., Bypassing the first-pass effect for the therapeutic use of cannabinoids, Pharmacol Biochem Behav, 44:745-747 (1993); Ohlsson, Lindgren, Whlen, Agurell, Hollister, Gillespie, Plasma delta-9-hydrocannabinol concentration and clinical effects after oral and intravenous administration and smoking, Clin Pharmacol Ther (1980), supra; PDR, 2000; Perlin, E., Smith, C. G., Nichols, A. I., Almirez, R., Flora, K. P., Cradock, J. C., Peck, C.C., Disposition and bioavailability of various formulations of tetrahydrocannabinol in the rhesus monkey, J Pharm Sci, 74:171-174 (1985)). There is also the difficulty of taking an oral medication during nausea and vomiting.
In contrast, inhalation of marijuana smoke (as some cancer patients do to alleviate nausea and vomiting due to chemotherapy) results in the rapid delivery of a systemic dose of xcex949 THC while avoiding the first-pass metabolism. Bamett C., Chiang, C., Perez-Reyes, M., Owens, S., Kinetic study of smoking marijuana, J Pharmacokin Biopharm, 10, 495-506 (1982); Chiang, C. W., Barnett, G., Marijuana effect and delta-9-tetrahydrocannabinol plasma level, Clin Pharmacolo Ther, 36,234-238 (1984); Cone, E., Huestis, M., Relating blood concentrations of tetrahydrocannabinol and metabolites to Few pharmacologic effects and time of marijuana usage, Ther Drug Mon, 15:527-532 (1993); Huestis, M. A., Sampson, A. H., Holicky, B. J., Henningfield, J. E., Cone, E. J., Characterization of the absorption phase of marijuana smoking, Clin Pharmacol Ther, 52:31-41 (1992); Johansson, E., Ohlsson, A., Lindgren, J. E., Agurell, S., Gillespie, H., Hollister, L. E., Single-dose kinetics of deuterium-labelled cannabinol in man after intravenous administration and smoking, Biomed Environ Mass Spectrom, 14:495-499 (1987); Ohlsson, A., Lindgren, J. E., Wahlen, A., Agurell, S., Hollister, L. E., Gillespie, H. K., Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking, Clin Pharmacol Ther, 28:409-16 (1980). Thus a patient would be expected to have better control by using the smoking route than from an orally administered gel capsule. However, inhalation of marijuana smoke exposes the user to mutagens, carcinogens, and other harmful by-products of pyrolysis. Hiller, F. C., Wilson, F. J. J., Mazumder, M. K., Wilson, J. D., Bone, R. C., Concentration and particle size distribution in smoke from marijuana cigarettes with different xcex949-tetrahydrocannabinol content, Fundam Appl Toxicol, 4:451-454 (1984); Matthias, P., Tashkin, D. P., Marques-Magallanes, J. A., Wilkins, J. N., Simmons, M. S., Effects of Varying Marijuana Potency on Deposition of Tar and xcex949-THC in the Lung During Smoking, Pharmacol Biochem Behav, 58:1145-1150 (1997). In heavy users, marijuana smoke causes bronchial irritation and impaired airway conductance (Henderson, R., Tennant, F., Guemey, R., Respiratory manifestations of hashish smoking, Arch Otol, 95:248-251 (1972); Tashkin, D., Shapiro, B., Lee, Y., Harper, C., Subacute effects of heavy marijuana smoking on pulmonary function in healthy men, N Eng J Med, 294:125-129 (1976)), as well as depressed alveloar macrophage bactericidal activity (Huber, G. L., Simmons, G. A., McCarthy, C. R., Cutting, M. B., Laguarda, R., Pereira, W., Depressant effect of marijuana smoke on antibactericidal activity of pulmonary alveolar macrophages, Chest, 68:769-73 (1975)). Another concern is the presence of numerous untested chemicals in the smoke. In addition to xcex949 THC, marijuana contains at least 60 cannabinoids and over 400 total chemical constituents (Ross, S., Elsohyl, M., Constituents of Cannabis saliva L., XXVIII, A review of the natural constituents: 1980-1984, Zagazig J Pharm Sci, 4:1-10 (1995); Turner, C., Bouwsma, O., Billets, S., Elsohly, M., Constituents of Cannabis saliva L. XCIIIxe2x80x94Electron voltage selected ion monitoring study in cannabinoids, Biomed Mass Spectrom, 7:247-256 (1980)), increasing the likelihood of multiple drug interactions. Further, marijuana remains illegal in most jurisdictions. Inhalation of marijuana smoke is thus not a particularly desirable treatment.
The Institute of Medicine (IOM) recently reviewed the scientific evidence for the potential of marijuana and its cannabinoid constituents to act as therapeutic agents. Joy, J., Watson Jr., S., Benson, J. E., Marijuana and Medicine: Assessing the Science Base (Washington, D.C.: National Academy Press, 1999). This report concluded that there is a potential for cannabinoid drugs, mainly xcex949 THC, for alleviation of pain, control of nausea and vomiting, and stimulation of appetite. However, they pointed out that marijuana is a xe2x80x9ccrude xcex949xe2x80x94THC delivery systemxe2x80x9d that delivers harmful chemicals along with the delivery of xcex949 THC, and recommended instead the development of a rapid-onset, reliable, and safe delivery xcex949 THC system. The House of Lords Select Committee on Science and Technology (Ninth Report) made similar suggestions to the British Government (House-of-Lords-Select-Committee-on-Science-and-Technology, 1998). Although the scheduling of cannabis has not been changed by the British or U.S. governments, the U.S. FDA has rescheduled MARINOL to a Schedule 3 drug, thus increasing the feasibility of developing other delivery forms of the drug.
There is no currently available pharmaceutically acceptable aerosol form of xcex949 THC. It would be advantageous to have available a form of pharmaceutical grade xcex949 THC that could be administered as an aerosol. This would provide a means for rapid uptake of the drug. Also, the potential adverse side effects encountered by smoking marijuana would be avoided. Further, an aerosol preparation of pharmaceutically pure xcex949 THC could be administered in known, controlled dosages. In 1976, Olsen et al. described a chlorofluorocarbon (CFC) propelled MDI formulation of xcex949 THC. Olsen, J. L., Lodge, J. W., Shapiro, B. J. and Tashkin, D. P. ,An inhalation aerosol of xcex949-tetrahydrocannabinol. J Pharmacy and pharmacol., 28:86 (1976). However, xcex949 THC is known to deteriorate during storage, and the stability of xcex949 THC in this formulation is suspect. In addition, the ethanol content in this formulation was so high (xcx9c23%) as to create an aerosol with droplets too large to be effectively inhaled. Dalby, R.N. and Byron, P. R., Comparison of output particle size distributions from pressurized aerosols formulated as solutions or suspensions, Pharm. Res. 5:36-39 (1988). The xcex949 THC CFC formulations were tested for use in treating asthma but were shown to be only moderately effective. Tashkin, D. P., Reiss, S., Shapiro, B. J., Calvarese, B., Olsen, J. L. and Lidgek, J. W., Bronchial effects of aerosolized xcex949-tetrahydrocannabinol in healthy and asthmatic subjects, Amer. Rev. of Resp. Disease. 115.:57-65 (1977); Williams, S. J., Hartley, J. P. R. and Graham, J. D. P., Bronchodilator effect of delta-9-THC administered by aerosol to asthmatic patients. Thorax. 31:720-723 (1976). Moreover, CFC propellants have since been banned so that a CFC propellant alternative would be particularly useful. It would clearly be advantageous to develop new aerosol formulations using a non-CFC propellant and having other advantageous features.
To date, much of the xcex949-THC aerosol exposure in humans concentrates on the bronchodilation effects of xcex949-THC. Tashkin et al. (1977) used a xcex949-THC MDI to deliver aerosolized xcex949-THC to healthy and asthmatic patients in an effort to assess bronchodilation as well as possible side effects due to systemic absorption. Tashkin, D. P., Reiss, S., Shapiro, B. J., Calvarese, B., Olsen, J. L., Lodge, J. W., Bronchial effects of aerosolized delta-9-tetrahydrocannabinol in healthy and asthmatic subjects, Am Rev Respir Dis, 115:57-65 (1977). In healthy patients, bronchodilation was seen, as well as substantial systemic side effects (increased heart rate and subjective reports of being xe2x80x98highxe2x80x99) at higher doses. However, in some asthmatic patients, bronchoconstriction occurred. Tashkin et al. suggested that large particle size of the xcex949-THC aerosol may have caused the local irritant effects. Vachon et al. (1976) reported the use of a nebulized xcex949-THC micro-aerosol to achieve bronchodilation without systemic effects, however, the propylene glycol vehicle had irritant effects. Vachon, J., Robins, A., Gaensler, E. A., Airways, response to aerosolized delta-9-tetrahydrocannabinol: preliminary report, in The therapeutic potential of marijuana, eds. Cohen, S., Stillman, R.C., pp. 111-121 (New York: Plenum Medical Book Co., 1976). Williams et al. (1976) also used a low concentration of xcex949-THC for bronchodilation without systemic side effects or detectable levels of xcex949-THC in the blood. Williams, S. J., Hartley, J. P., Graham, J. D., Bronchodilator effect of delta1-tetrahydrocannabinol administered by aerosol of asthmatic patients, Thorax, 6:720-723 (1976). It would clearly be advantageous to develop new aerosol formulations in which the xcex949 THC is stable, the droplets are of a size that can be effectively inhaled, and which use a non-CFC propellant.
Such objectives have been long desired but difficult to achieve, because of problems such as the difficulty of working with xcex949 THC, large dosage amounts required for xcex949 THC, and properties of xcex949 THC that make it unlike, and not interchangeable with, most other drugs. For example, xcex949 THC resembles rubber-cement, rather than a powder like most drugs, and thus presents formulation difficulties. Scientists working with THC found that they had to go to great lengths to combat its instability, based on its instability to light, oxygen, acids, bases, metal ions, etc. Thus, after the initial interest in the 1970s in THC/CFC aerosols, scientists generally settled into an acceptance of the unworkability of a THC aerosol. The initial promise of a THC aerosol according to J. L. Olsen, J. W. Lodge, B. J. Shapiro and D. P. Tashkin (1975) never materialized, and in the past few decades it has been conventionally thought that THC is not suited for aerosol-dispensing, and especially not for MDI-dispensing.
Thus, a pharmaceutically effective THC aerosol that overcomes the above-mentioned limitations of the prior art, especially an MDI-dispensible aerosol would be much desired.
The present inventors have now discovered, surprisingly, that THC dissolves well in HFA and that an aerosol-dispensable THC/HFA, pharmaceutical compositionxe2x80x94i.e., a sufficiently stable composition and at the high doses which are required for THCxe2x80x94may be formulated. The present invention exploits these surprising discoveries. It is an object of the present invention to provide a stable aerosol-dispensable pharmaceutical composition comprising a non-CFC propellant and a pharmaceutically effective concentration of xcex949 THC, and xcex949 THC derivatives (e.g., cannabinoids such as xcex948-tetrahydrocannabinol, 11-hydroxy xcex949-tetrahydrocannabinol, cannabinol, cannabidol, nabilone, levonantradol, (xe2x88x92)-HU-210, Win 55212-2, Anandamide, Methandamide, CP 55940, O-1057, SR141716A, etc.). More particularly, it is an object of the present invention to provide a stable aerosol-dispensable pharmaceutical composition comprising a hydrofluoroalkane propellant (for example, HFA 227 or HFA 134a) and xcex949 THC. The propellant is present in the range of approximately 78 to 100% by weight, and more particularly the propellant is present in the range of approximately 85 to 100% by weight. An organic solvent such as ethanol can be used to assist in solubilizing the xcex949 THC in the propellant but is not required. If a solvent is used, preferably less than 20% by weight will be required, and most preferably less than 15% by weight will be required. The pharmaceutically effective concentration of xcex949 THC is preferably in the range of 0.05 to 10% by weight, and most preferably in the range of 0.1 to 6% by weight. The pharmaceutical composition of the present invention can be used to treat a variety of medical conditions including nausea and vomiting associated with cancer chemotherapy, muscle spasticity, pain, anorexia associated with AIDS wasting syndrome, anorexia associated with cancer chemotherapy, epilepsy, glaucoma, bronchial asthma, mood disorders, migraine headaches.